Due to partial double bond character, isomerization of the peptide bond between the cis and trans states occurs at a very slow rate. This process becomes of special importance for ...X-pro... bonds in a polypeptide chain because the cis and trans forms are of nearly equal thermodynamic stability. Earlier studies have suggested that the rate-limiting step in the unfolding and refolding of small globular proteins is due to proline isomerization, and that the true conformational changes occur at a much faster time scale. More definitive information is being sought for two protein folding reactions- porcine trypsinogen and Rnase A. There are also suggestions that their structural processes may be controlled or influenced by proline isomerization in certain cases. These include subtle changes in the structure of native proteins, sterospecific synthesis of proteins on the ribosome, regulation of enzyme and hormone activity, etc. Before exploring these possibilities in detail, a method must be found which is capable of detecting isomerism when it occurs in proteins. Along these lines, two possibilities are being investigated. First, our studies have shown that proline-specific proteases recognize only the trans form of the ...X-Pro... bond so that isomerism can be followed indirectly by proteolysis. Second, we are attempting to find a specific catalyst for the process of proline isomerization.